2,5-二取代吲哚衍生物的合成及抗增殖活性研究
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摘要
以对硝基苯肼为起始原料,采用费舍尔吲哚合成法合成中间体5-硝基吲哚-2-羧酸酯(3),经还原合成5-氨基吲哚-2-羧酸酯(4),再与4-甲氧基-2-甲苯基异氰酸酯合成脲(5),(5)在水合肼作用下5-(3-(4-甲氧基-2-甲苯基)脲基)-1H-吲哚-2-碳酰肼(6),化合物6和取代醛反应,合成了6个2,5-二取代吲哚衍生物(7a～7f),其结构经~1HNMR,~(13)CNMR和HR-MS表征。采用MTT法研究了7a～7f对人肺癌细胞(A549)和人肝癌细胞(HepG-2)的体外抗增殖活性。结果显示:7d体外抑制活性最优,其IC_(50)分别为10.35μmol·L~(-1)、12.60μmol·L~(-1)。
The intermediate 5-nitroindole-2-carboxylate(3)was prepared by the Fisher indole synthesis method using p-nitrophenylhydrazine as the starting material,and 5-aminoindole-2-carboxylate(4)was obtained by reduction of compound(3).Then compound(4)reacted with 4-methoxy-2-methylphenyl isocyanate to afford urea(5).1H-Indole-2-carbohydrazide(6)was prepared from reaction of urea(5)with hydrazine hydrate.The target compounds 2,5-disubstituted indole derivatives(7 a～7 f)were synthesized of condensation of compound(6)with substituted aldehydes.The structures were characterized by ~1H NMR,~(13)C NMR and HR-MS.The antiproliferative activity in vitro of target compounds(7 a～7 f)against human lung cancer cells(A549)and human hepatoma cells(HepG-2)was evaluated by the MTT assay.The results showed that compound 4 n displayed the most potential antiproliferative activity with IC_(50) value of 10.35μmol·L~(-1) and 12.60 μmol·L~(-1)respectively.
The intermediate 5-nitroindole-2-carboxylate(3)was prepared by the Fisher indole synthesis method using p-nitrophenylhydrazine as the starting material,and 5-aminoindole-2-carboxylate(4)was obtained by reduction of compound(3).Then compound(4)reacted with 4-methoxy-2-methylphenyl isocyanate to afford urea(5).1H-Indole-2-carbohydrazide(6)was prepared from reaction of urea(5)with hydrazine hydrate.The target compounds 2,5-disubstituted indole derivatives(7 a～7 f)were synthesized of condensation of compound(6)with substituted aldehydes.The structures were characterized by ~1H NMR,~(13)C NMR and HR-MS.The antiproliferative activity in vitro of target compounds(7 a～7 f)against human lung cancer cells(A549)and human hepatoma cells(HepG-2)was evaluated by the MTT assay.The results showed that compound 4 n displayed the most potential antiproliferative activity with IC_(50) value of 10.35μmol·L~(-1) and 12.60 μmol·L~(-1)respectively.
引文
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[5]Zhang M Z,Chen Q,Yang G F.A review on recent developments of indole-containing antiviral agents[J].Eur J Med Chem,2015,89(2):421-441.
[6]Hu H,Wu J,Ao M,et al.Synthesis,structure-activity relationship studies and biological evaluation of novel 2,5-disubstituted indole derivatives as anticancer agents[J].Chem Biol Drug Des,2016,88(5):766-778.
[7]Hu H Y,Yu X D,Wang F,et al.Novel N-substituted 2-(2-(adamantan-1-yl)-1H-indol-3-yl)-2-oxoacetamide derivatives[J].Synth Biol Eval Mol,2016,21(5):1-15.
[8]Hu H,Lin C,Ao M,et al.Synthesis and biological evaluation of 1-(2-(adamantane-1-yl)-1H-indol-5-yl)-3-substituted urea/thiourea derivatives as anticancer agents[J].Rsc Adv,2017,7(81):51 640-51 651.
[9]Houlihan W J;Parrino V A,Uike Y.Lithiation of N-(2-alkylphenyl)alkanamides and related compounds.a modified madelung indole synthesis[J].J Org Chem,1981,46(22):4 511-4 515.
[10]Robinson M W,Overmeyer J H,Young A M,et al.Synthesis and evaluation of indole-based chalcones as inducers of methuosis,a novel type of nonapoptotic cell death[J].J Med Chem,2012,55(5):1 940-1 956.
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[12] 冯流星,丁绍民,宋华付.吲哚-2-羧酸的合成工艺研究[J].化学与粘合,2003,(4):196-197.
[13] 杨艳芳,林娟娟,李雪华,等,1,3-双苯并咪唑银配合物的合成、抗肿瘤活性及与 DNA的相互作用研究[J].化学研究与应用,2018,30(7):1 106-1 113.
[14] 莫松,丁勇,张刚,等.含 1-[4-二-(4-氟苯)甲基]哌嗪官能团的 1,2,3-三氮唑衍生物的合成及抗肿瘤活性研究[J].化学研究与应用,2017,29(11):1 635-1 640.